In many neurodegenerative diseases including Alzheimer's disease and Parkinson's disease, abnormal protein structures that accumulate in the nerve cells are found in the patients' brains, and formation of these abnormal structures is considered to be closely related to the onset of the diseases. In the cases of neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), ubiquitin-positive inclusions emerge in the nerve cells of the patient's brain (FIG. 1). Since the emerging sites of the inclusions are found to correspond to the sites with loss of nerve cells, emergence of these intracellular inclusions is considered to cause nerve cell death and eventually lead to the onset of the diseases. In the recent research, the present inventors have identified a nuclear protein called TAR DNA-binding protein of 43 kDa (TDP-43) as a primary component of the intracellular inclusions found in the FTLD or ALS patients' brain (Arai T et al., TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis, Biochem. Biophys. Res. Commun., 2006, vol. 351(3), p. 602-611; Neumann M et al., Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis, Science, 2006, vol. 314(5796), p. 130-133). TDP-43 is a protein that is localized in the nucleus and considered to be involved in transcriptional regulation and the like (Buratti E et al., Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping, EMBO J., 2001, vol. 20(7), p. 1774-1784), but little is known about its actual functions.
Among ALS, i.e., intractable nerve diseases that progress very fast, about 5-10% are familial ALS and the resulting majorities are presumed to be sporadic ALS. Among familial ALS, approximately 20% are cases associated with genetic abnormality of superoxide dismutase 1 (SOD1) (Deng H X et al., Amyotrophic lateral sclerosis and structural defects in Cu, Zn superoxide dismutase, 1993, Science, vol. 261, p. 1047-1051; Rosen D R et al., Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis, 1993, Nature, vol. 362, p. 59-62). While many reports have been made as to the association between SOD1 abnormality and the onset, it is also suggested that it has different neuropathological characteristics from sporadic ALS. Specifically, while TDP-43-positive inclusions are observed in the sporadic ALS patients' brains in almost all cases (Geser F et al., Evidence of multisystem disorder in whole-brain map of pathological TDP-43 in amyotrophic lateral sclerosis, 2008, Arch. Neurol., vol. 65, p. 636-641; Nishihira Y et al, Sporadic amyotrophic lateral sclerosis: two pathological patterns shown by analysis of distribution of TDP-43-immunoreactive neuronal and glial cytoplasmic inclusions, 2008, Acta. Neuropathol., vol. 116, p. 169-182), ubiquitin-positive inclusions found in familial ALS patients' brains with SOD1 mutation are not stained with anti-TDP-43 antibody (Mackenzie I R et al, Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations, 2007, Ann. Neurol., vol. 61, p. 427-434; Tan C F et al, TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation, 2007, Acta. Neuropathol., vol. 113, p. 535-542). These facts suggest that familial ALS associated with SOD1 mutation has different onset mechanism from the rest of familial ALS and the predominant sporadic ALS. In light of the above-described discovery of the TDP-43 gene mutation in the ALS patients, TDP-43 abnormality appears to be the primary factor of the onset of majority of ALS, and its intracellular aggregation is closely related to the onset.
Thus, elucidation of how TDP-43 protein is accumulated in the cells by what kind of mechanism and how it exerts cytotoxicity, in other words, elucidation of the mechanism of intracellular TDP-43 inclusion formation and the neurodegenerative mechanism caused by the inclusions would be a huge contribution not only to the elucidation of the onset mechanisms of ALS and FTLD (elucidation of the cause of the diseases) but also to the development of a therapeutic drug and method for them.